The long-term goal of the proposed study is to elucidate neural mechanisms and cognitive processes mediating genetic influences on substance use vulnerability in adolescents. Research suggests a common genetic liability to substance use, the externalizing spectrum of psychopathology, and impulsive personality traits. We hypothesize that etiological pathways from genes to substance use involve a dysfunction in basic neurocognitive processes underlying executive control of behavior including action monitoring, response inhibition, decision making, and executive attention. This proposal seeks to test this etiological pathway hypothesis through the integration of developmental, genetic, and cognitive neuroscience approaches. We propose a prospective longitudinal study of twins (180 MZ and 180 DZ pairs), their siblings (n=120), and parents. Laboratory experiments will focus on brain electrophysiological indices of cognitive control that have been linked to specific regions of the prefrontal and anterior cingulate cortex in recent studies. Using these measures, we will assess three consecutive cohorts of 12-year-old twins, i.e. prior to the typical onset of substance use, and follow them up through the most vulnerable period of adolescence, with full assessments at 14 and 16 years. Diagnostic assessments will include semi-structured interviews and questionnaires. Specific aims will be 1) to assess the influence of genetic and environmental factors on neurocognitive mechanisms of inhibitory control during adolescence; 2) to determine the extent to which heritable markers of disinhibition prospectively predict substance use behavior and comorbid psychopathology; 3) to characterize developmental changes of the neurocognitive mechanisms underlying inhibitory self-control and to determine whether substance use during adolescence alters normal neurocognitive development. The proposed study should contribute to bridging the gap between the genotype and complex behavioral outcomes, provide important neurocognitive endophenotypes for future genetic studies of drug abuse, and increase our understanding of neurodevelopmental pathways leading to increased vulnerability to substance abuse.